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Structure of 39827-11-7 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With thionyl chloride In toluene at 20℃; for 8 h; Reflux
Benzo[b]thiophene-2-carbonyl chlorid[0104] Thianaphthene-2-carboxylic acid (356.42 mg, 2 mmol) was suspended in dry toluene (6 mL), thionyl chloride (4.4 mL, 60 mmol) and DMF (0.05 mL) were added at room temperature, and then the mixture was refluxed 8 h.4 The volatiles were removed at reduced pressure gave benzo[b]thiophene-2-carbonyl chloride as a yellow power. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :9) as eluent, give 3 as a white power (393.64 mg, 94.9percent). Spectral data were in accordance with those published.1H-NMR (300 MHz, CDCls): δ 8.31 (s, 1H), 7.04-7.89 (m, 2H), 7.60-7.46 (m, 2H. 13C NMR (300 MHz, CDC13): δ 161.14, 144.07, 138.05, 136.59, 135.89, 128.75, 126.68, 125.66, 122.91.
61%
With pyridine; thionyl chloride In tolueneReflux
Thionyl chloride (0.81 mL, 11.1 mmol) was added to a solution of benzo[b]thiophene-2-carboxylic acid 3 (0.4 g, 2.24 mmol), in pyridine (0.3 mL, 1.8 mmol) and toluene (15 mL, 14.1 mmol) at reflux. The reaction mixture was quenched in ice water and the toluene evaporated in vacuo. The acid chloride was extracted with distilled DCM (2.x.25 mL, 2.x.10 mL) and the combined organic extracts washed with distilled water (2.x.20 mL) and dried. The solvent was evaporated under reduced pressure to give a brown residue, which was purified using flash chromatography with DCM as the eluent to yield 11a17 (0.27 g, 61percent) as a colourless solid. 1H NMR (CDCl3, 300 MHz): δ 7.50 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). 13C NMR: δ 123.1 (C3), 125.9 (C7), 126.9 (C4), 128.9 (C5 and C6), 136.1 (C2), 138.3 (C3a), 144.3 (C7) and 161.9 (CO). MS (CI+), m/z 197, 199 [MH+1, 35Cl, 37Cl].
1.1 g
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1 h;
To a 100-mL round-bottom flask was placed a solution of 1-benzothiophene-2-carboxylic acid (1.0 g,5.61 mmol)in DCM (30 mL) followed by the dropwise addition of oxalyl chloride (1.426 g,11.23 mmol) with stirring at 0°C. To the solution was added DMF (0.01 mL) then the reaction was stirred for 1H at a The solvent was removed under reduced pressure affording 1.1 g of 1-benzothiophene-2-carbonyl chloride as a yellow solid.
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 11, p. 3764 - 3767
[2] Patent: WO2012/99785, 2012, A2, . Location in patent: Page/Page column 25
[3] Tetrahedron Asymmetry, 2003, vol. 14, # 3, p. 339 - 346
[4] Organometallics, 2015, vol. 34, # 12, p. 3065 - 3071
[5] Journal of the American Chemical Society, 2005, vol. 127, # 43, p. 15010 - 15011
[6] Tetrahedron, 2011, vol. 67, # 36, p. 6895 - 6900
[7] Journal of Medicinal Chemistry, 1984, vol. 27, # 5, p. 570 - 576
[8] European Journal of Medicinal Chemistry, 2004, vol. 39, # 1, p. 85 - 97
[9] Journal of Medicinal Chemistry, 2005, vol. 48, # 3, p. 839 - 848
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 2074 - 2079
[11] Journal of Medicinal Chemistry, 2007, vol. 50, # 8, p. 1850 - 1864
[12] Patent: WO2006/91674, 2006, A1, . Location in patent: Page/Page column 87
[13] Patent: US5244893, 1993, A,
[14] Patent: US5304657, 1994, A,
[15] Heterocycles, 2008, vol. 75, # 8, p. 1913 - 1929
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[17] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7249 - 7257
[18] Chemical Communications, 2010, vol. 46, # 13, p. 2289 - 2291
[19] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 265 - 274
[20] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3581 - 3594
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[23] Synthetic Communications, 2013, vol. 43, # 3, p. 337 - 344
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[25] European Journal of Medicinal Chemistry, 2013, vol. 66, p. 489 - 498
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[27] Organic Letters, 2017, vol. 19, # 23, p. 6332 - 6335
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[30] Patent: WO2016/100184, 2016, A1, . Location in patent: Paragraph 00691-00693
[31] Patent: KR2016/21163, 2016, A, . Location in patent: Paragraph 0890; 0892
[32] Patent: KR2015/25531, 2015, A, . Location in patent: Paragraph 0890; 0891; 0892
[33] Patent: CN103961348, 2016, B, . Location in patent: Paragraph 0039; 0051; 0052
[34] Organic Letters, 2017, vol. 19, # 12, p. 3091 - 3094
[35] Molecules, 2017, vol. 22, # 8,
[36] Patent: WO2017/62581, 2017, A1, . Location in patent: Paragraph 0313
[37] Synlett, 2017, vol. 28, # 19, p. 2594 - 2598
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[42] Patent: WO2018/231635, 2018, A1, . Location in patent: Paragraph 0045; 0047
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 3768,3769[2] Journal of the American Chemical Society, 1949, vol. 71, p. 2856,2857
5
[ 39827-11-7 ]
[ 89673-36-9 ]
Reference：
[1] Synthesis, 1983, # 11, p. 932 - 933
With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 20℃; for 8h;Reflux;
Benzo[b]thiophene-2-carbonyl chlorid[0104] Thianaphthene-2-carboxylic acid (356.42 mg, 2 mmol) was suspended in dry toluene (6 mL), thionyl chloride (4.4 mL, 60 mmol) and DMF (0.05 mL) were added at room temperature, and then the mixture was refluxed 8 h.4 The volatiles were removed at reduced pressure gave benzo[b]thiophene-2-carbonyl chloride as a yellow power. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (1 :9) as eluent, give 3 as a white power (393.64 mg, 94.9%). Spectral data were in accordance with those published.1H-NMR (300 MHz, CDCls): delta 8.31 (s, 1H), 7.04-7.89 (m, 2H), 7.60-7.46 (m, 2H. 13C NMR (300 MHz, CDC13): delta 161.14, 144.07, 138.05, 136.59, 135.89, 128.75, 126.68, 125.66, 122.91.
61%
With pyridine; thionyl chloride; In toluene;Reflux;
Thionyl chloride (0.81 mL, 11.1 mmol) was added to a solution of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> 3 (0.4 g, 2.24 mmol), in pyridine (0.3 mL, 1.8 mmol) and toluene (15 mL, 14.1 mmol) at reflux. The reaction mixture was quenched in ice water and the toluene evaporated in vacuo. The acid chloride was extracted with distilled DCM (2×25 mL, 2×10 mL) and the combined organic extracts washed with distilled water (2×20 mL) and dried. The solvent was evaporated under reduced pressure to give a brown residue, which was purified using flash chromatography with DCM as the eluent to yield 11a17 (0.27 g, 61%) as a colourless solid. 1H NMR (CDCl3, 300 MHz): delta 7.50 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). 13C NMR: delta 123.1 (C3), 125.9 (C7), 126.9 (C4), 128.9 (C5 and C6), 136.1 (C2), 138.3 (C3a), 144.3 (C7) and 161.9 (CO). MS (CI+), m/z 197, 199 [MH+1, 35Cl, 37Cl].
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane;
(+/-)-fralphan5-l-(Benzo[b]thiophene-2-carbonyl)-2-methyl-l,2,3,4-tetrahydro-quinoline-4- carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting benzo[b]thiophene-2-carbonyl chloride for 4-trifluoromethyl-benzoyl chlorided. Benzo[b]thiophene-2-carbonyl chloride was prepared by reaction of thianaphthene-2-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. The crude l-(benzo[b]thiophene-2-carbonyl)-2- methyl-l,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (1% methanol / methylene chloride) followed by purification via HPLC yielded (+/-)-/rans-2-methyl-l-(pyrimidine-5- carbonyl)-l,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (34%). 1H-NMR (CDCl3) delta: 1.02 - 1.18 (m, 6H), 1.65 - 1.75 (m, IH), 2.55 - 2.65 (m, IH), 3.60 - 3.70 (m, IH),3.80 (q, 2H), 5.05 - 5.15 (m, IH), 6.70 (d, IH), 6.80 - 7.00 (m, 3H), 7.20 -7.40 (m, 4H), 7.45 (s, IH),7.50 (d, 2H), 7.70 (d, IH), 7.80 (d, IH). MS m/z: 489/491 (M+l).
With thionyl chloride; In hexane;
To 57.5 g (0.324 mol) of benzothiophene-2-carboxylic acid in 600 ml of chlorobenzeno there are added dropwise with stirring at reflux temperature 57.8 g (0.468 mol) of thionyl chloride and, when the addition is complete, the mixture is stirred at reflux temperature until the evolution of gas has ceased. For working up, the reaction mixture is allowed to cool to room temperature and then concentrated in vacuo, the residue is stirred with n-hexane, and precipitate which has settled out is filtered off with suction and dried. 57.4 g (90% of theory) of benzothiophene-2-carboxylic acid chloride, which can be reacted further without additional purification, are obtained. STR11
With thionyl chloride;
(1) 1.0 g of <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> was reacted with 2 ml of thionyl chloride under reflux overnight, and then excess thionyl chloride was distilled off under reduced pressure to obtain benzo[b]thiophene-2-carbonyl chloride as a solid product.
With thionyl chloride; for 2h;Reflux;
General procedure: Compounds 1, 2, 3, 4 and 5 were commercially available. Compounds 6, 7, 8, 9 and 10 were prepared from the corresponding carboxylic acid (9.18 mmol) and thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With thionyl chloride; for 2h;Reflux;
General procedure: The heteroaryl acyl chlorides used in the synthesis of compounds 1b, 2b, 3b, 4b and 5b were commercially available. For compounds 6b, 7b, 8b, 9b and 10b, the chloride derivatives were prepared from the corresponding carboxylic acid (9.18 mmol) nd thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With thionyl chloride;Reflux;
Compound 9a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide (328 mg, 1.5 mmol was addedfollowed by triethylamine (TEA; 0.42 mL, 3 mmol). The reactionmixture was stirred at room temperature. After the reaction wascompleted, the reaction mixture was diluted with CH2Cl2 andsequentially washed with water, 1 N HCl and saturated NaHCO3.The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane/ethyl acetate (EtOAc) = 4:1 to obtain 10a, (236 mg,76%) as white solid.
With thionyl chloride; at 60℃; for 2h;
A mixture of carboxylic acid in thionyl chloride (5 mL/mmol carboxylic acid) was stirred at 60 C for 2 hours. On completion, the solution was concentrated in vacuo to give the acid chloride, which was used directly without further purification. This material (1.1 eq) was added to a mixture of racemic amine (1 eq.) and triethylamine (2 eq.) in dichloromethane (3-5 mL/mmol racemic amine) at room temperature. The mixture was stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC to give racemic amide product. Following general procedure A, rac-1 was prepared from benzo[b]thiophene-2 -carboxylic acid and rac-A-104 (0.10 g, 0.65 mmol). The product was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini C 18 150x30 mm, particle size: 5 mupiiota; Mobile phase: 35-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give rac-1 (0.15 g, 73% yield) as a white solid. LCMS : (ES+) m/z (M+H)+ = 315.1.
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 50℃; for 0.333333h;
Benzo[b]thiophene-2-carboxylic acid (50 mg, 0.28 mmol)dichloromethane (3 mL) It was dissolved in thionyl chloride (SOCl2, 0.50 mL)and dimethylformamide (2 drops) It was added thereto, and was stirred for 20 minutes at 50C . Thereafter, the reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL)after the diluted, quinolin-3-amine (50.0 mg, 0.347 mmol)and triethyl amine was added and stirred for a (100 mg, 0.988 mmol) and 15 hours at room temperature. Thin film chromatography (TLC) in verifying, new the spot location changes accordingly once created, reaction mixture of decompressing concentrated within, fraction is concentrated tosilica gel thin chromatography (preparative TLC, n/ethyl acetate = 2/1-hexanediol) for purifying the white solid thereby, a desired compound (23.0 mg, 27%) is obtained.
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 50℃; for 0.333333h;
Benzo [b] thiophene-2-carboxylic acid (50 mg, 0.28 mmol) and dichloromethane (3 mL) was dissolved in thionyl chloride (SOCl2, 0.50 mL) and dimethylformamide (2 drops) after the addition, the mixture was stirred for 20 minutes at 50 .Thereafter, the reaction mixture was concentrated under reduced pressure, dichloromethane (3 mL) and then diluted to, quinolin-3-amine (50.0 mg, 0.347 mmol) and triethylamine (100 mg, 0.988 mmol) was added to 15 at room temperature and and it stirred for hours. When the thin film check chromatography (TLC), when a new spot is generated, to give the mixture was concentrated under reduced pressure, and purified by silica gel preparative thin layer chromatography (preparative TLC, ethyl acetate / n- hexane = 2/1), the reaction mixture is object of a white solid to give the compound (23.0 mg, 27%).
With thionyl chloride; In dichloromethane; at 20℃;Inert atmosphere; Reflux;
General procedure: At low temperature conditions,The thionyl chloride was slowly added to the solution of compound 4 in anhydrous dichloromethane,After dripping,The reaction was returned to room temperature and refluxed under nitrogen.After the reaction is complete,Steaming all solvents,Then dissolved in anhydrous tetrahydrofuran or anhydrous dichloromethane,Compounds 3 and pyridine were added at low temperature,The reaction was transferred to room temperature and overnight.To the reaction system by adding water,And extracted three times with ethyl acetate,Combine organic phase,Washed three times with saturated sodium bicarbonate solution and saturated brine,Dried over anhydrous sodium sulfate and subjected to column chromatography to give compound 6.
With thionyl chloride;Reflux;
General procedure: Following a described procedure [24,42,43] with a few modifications, sodium borohydride wasslowly added to a suspension of selenium powder in water at room temperature or in ethanol, N2atmosphere and 0 C, and stirred until the formation of the typical colorless solution of NaHSe. Then,the corresponding aroyl or heteroaroyl chloride was added. Temperature and time of reaction varieddepending on the compounds. Methylation was achieved through the addition of methyl iodide(in excess). Purification was performed by several washings, recrystallization in different solvents orcolumn chromatography. In those cases where the acyl chloride was not available, it was formed bythe reaction of the corresponding carboxylic acid with SOCl2 for 1-8 h at reflux. Solvent was removedunder vacuum by rotatory evaporation, and the product was then washed three times with dry toluene,which was also eliminated by rotatory evaporation.
1.1 g
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h;
To a 100-mL round-bottom flask was placed a solution of 1-benzothiophene-2-carboxylic acid (1.0 g,5.61 mmol)in DCM (30 mL) followed by the dropwise addition of oxalyl chloride (1.426 g,11.23 mmol) with stirring at 0C. To the solution was added DMF (0.01 mL) then the reaction was stirred for 1H at a The solvent was removed under reduced pressure affording 1.1 g of 1-benzothiophene-2-carbonyl chloride as a yellow solid.
With thionyl chloride; for 2h;Reflux;
General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide.
With thionyl chloride;Reflux;
General procedure: Compound 28a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide(328 mg, 1.5 mmol was added followed by triethylamine (TEA;0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature.After the reaction was completed, the reaction mixture was dilutedwith CH2Cl2 and sequentially washed with water, 1 N HCl and saturatedNaHCO3. The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane: Ethyl acetate (EtOAc)=4:1 to obtain 29a,(236 mg, 76%) as white solid.
With thionyl chloride; for 3h;Reflux;
To a dry 25mL round bottomed flask was added 44mg (0.25mmol) <strong>[6314-28-9]benzo[b]thiophene-2-carboxylic acid</strong> and excess (5mL) thionyl chloride, and the resulting mixture held at reflux for 3h. The resulting benzo[b]thiophene-2- carbonyl chloride was then evaporated to dryness via rotavap in preparation for the next step.
Stage #1: 2-carbethoxyindole With tin(IV) chloride In dichloromethane at 0 - 20℃; for 0.5h;
Stage #2: benzo<b>thiophene-2-carboxylic acid chloride In nitromethane; dichloromethane at 20℃; for 40h;
14b
To a stirred solution of indole-2-carboxylic acid ethyl ester (1.0 g, 5.29 mmol) in CH2Cl2 (10 mL) was added tin (IV) chloride (5.82 mL, 5.82 mmol) at 0° C. The reaction was stirred at room temperature for 30 min. A solution of benzo[b]thiophene-2-carbonyl chloride (1.04 g, 5.29 mmol) in CH3NO3 (7.5 mL) was added and stirred for 40 h. The reaction was poured into an ice-water (30 mL) and warmed to room temperature. The reaction mixture was extracted with CH2Cl2 (50 mL*3). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (Hexanes/EtOAc 3:1) to give 1.45 g (78%) of compound 13b. 500 mg of compound 13b was heated to reflux with H2NNH2-H2O in ethylene glycol (10 mL) for 1 h. After cooled to room temperature, the precipitate was collected by filtration, washed with EtOH, dried under vacuum to give 158 mg (35%) of Example 14b. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 13.07 (s, 1H), 8.09-8.02 (m, 3H), 7.95 (m, 1H), 7.69 (m, 1H), 7.55-7.46 (m, 3H), 7.27 (m, 1H) ppm; MS (m/e) 318 (M+1).
S-(6,6-difluoro-5-methyl-5-hexenyl) benzo[b]thiophene-2-thiocarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With triethylamine In tetrahydrofuran at 20℃; for 1h;
13 Production Example 13; Production of compound (53) by the production method 2
Production Example 13; Production of compound (53) by the production method 2; To 10 ml of tetrahydrofuran were dissolved 0.25 g (1.5 mmol) of 6, 6-difluoro-5-methyl-5-hexene-1-thiol and 0.39 g (2.0 mmol) of benzo[b]thiophene-2-carbonylchloride, followed by the drop-wise addition of 0.30 g (3.0 mmol) of triethylamine at room temperature, followed by stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purifiedwith silica gel column chromatography (diisopropyl ether : hexane = 1 : 20) to obtain 0.39 g (yield: 80 %) of S-(6,6-difluoro-5-methyl-5-hexenyl) benzo[b]thiophene-2-thiocarboxylate.1H-NMR (CDCl3, TMS) δppm: 1.50-1.60 (5H, m), 1.65-1.75 (2H, m), 1.99-2.05 (2H, m), 3.13(2H, t), 7.38-7.49 (2H, m), 7.85-7.90 (2H, m), 8.05 (1H, s)
With sodium carbonate; In water; at 0 - 20℃; for 15h;
To a 1 M Na2CO3 solution (5 mL) at 0 C was added <strong>[110117-84-5]D-3-fluorophenylalanine</strong> (0.5 g, 2.73 mmol) and 1-benzothiophene-2-carbonyl chloride (62 mg, 0.316 mmol). After 15 h at 20 C, the mixture was acidified by addition of ice-cold 5% HCl solution (10 mL). The suspension was extracted with methylene chloride (3x25 mL). The combined organic layers were dried over MgS04 and concentrated to yield 0.6 G of 87 as a white solid. The carboxylic acid 87 was dissolved in THF (5 mL). To the THF solution at 0 C was added 1 M borane in THF (1.31 mL). After 15 h at 25 C, a sat'd NaHCO3 solution (15 mL) was introduced. The suspension was stirred for 3 h and then extracted with methylene chloride (3x25 mL). The combined organic layers were washed with brine (2x25 mL), dried over Na2SO4, and concentrated. Purification by column chromatography (35% EtOAc in hexanes) gave 200 mg (22. 5% yield) of the compound 88. 1H NMR (CDCI3) : delta 7.84 (2H, m), 7.72 (1H, s), 7.41 (2H, m), 7.34-7. 25 (1H, m), 7. 11-6. 89 (3H, m), 6.41 (1H, br d, J=7.5 Hz), 4.37 (1 H, m), 3.77 (2H, m), 3.03 (2H, AB), 2.33 (1 H, br s).
To a 1 M Na2CO3 solution (5 mL) at 0 C. was added <strong>[110117-84-5]D-3-fluorophenylalanine</strong> (0.5 g, 2.73 mmol) and 1-benzothiophene-2-carbonyl chloride (62 mg, 0.316 mmol). After 15 h at 20 C., the mixture was acidified by addition of ice-cold 5% HCl solution (10 mL). The suspension was extracted with methylene chloride (3×25 mL). The combined organic layers were dried over MgSO4 and concentrated to yield 0.6 g of 87 as a white solid. The carboxylic acid 87 was dissolved in THF (5 mL). To the THF solution at 0 C. was added 1 M borane in THF (1.31 mL). After 15 h at 25 C., a sat'd NaHCO3 solution (15 mL) was introduced. The suspension was stirred for 3 h and then extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine (2×25 mL), dried over Na2SO4, and concentrated. Purification by column chromatography (35% EtOAc in hexanes) gave 200 mg (22.5% yield) of the compound 88. 1H NMR (CDCl3): delta 7.84 (2H, m), 7.72 (1H, s), 7.41 (2H, m), 7.34-7.25 (1H, m), 7.11-6.89 (3H, m), 6.41 (1H, brd, J=7.5 Hz), 4.37 (1H, m), 3.77 (2H, m), 3.03 (2H, AB), 2.33 (1H, br s).
With triethylamine In dichloromethane at 20℃; for 1h;
69 Alcohol 69
Amine 68 (1. 05 g, 5.72 mmol) was dissolved in CH2CI2 (60 mL). Triethylamine (0.88 mL, 6.30 mmol) was added, followed by benzo [b] thiophene-2-carbonyl chloride (1.12 g, 5. 72 mmol). The reaction was stirred at room temperature for one hour, and the solvent was removed in vacuo. The product was purified by flash column chromatography eluting with a gradient of 30-60% EtOAc/hexanes (Rf = 0.24 (50% EtOAc/hexanes) to give 1.87 g (91%0 of a white solid 69. 1H NMR (DMSO-d6) : δ 1.68-1.75 (m, 2H), 2.87 (d, 2H, J=7. 0 Hz), 3.43-3.52 (m, 2H), 4.20-4.27 (m, 1H), 4.42 (t, 1H, J=5. 1 Hz), 6.94-7.00 (m, 1H), 7.03-7.08 (m, 2H), 7.25-7.32 (m, 1H), 7.39-7.46 (m, 2H), 7.90- 8.01 (m, 2H), 8.05 (s, 1H), 8.50 (d, 1H, J=8.5 Hz); LCMS 344 (M+H).
91%
With triethylamine In dichloromethane at 20℃; for 1h;
69
Amine 68 (1.05 g, 5.72 mmol) was dissolved in CH2Cl2 (60 mL). Triethylamine (0.88 mL, 6.30 mmol) was added, followed by benzo[b]thiophene-2-carbonyl chloride (1.12 g, 5.72 mmol). The reaction was stirred at room temperature for one hour, and the solvent was removed in vacuo. The product was purified by flash column chromatography eluting with a gradient of 30-60% EtOAc/hexanes (Rf=0.24 (50% EtOAc/hexanes) to give 1.87 g (91%) of a white solid 69. 1H NMR (DMSO-d6): δ 1.68-1.75 (m, 2H), 2.87 (d, 2H, J=7.0 Hz), 3.43-3.52 (m, 2H), 4.20-4.27 (m, 1H), 4.42 (t, 1H, J=5.1 Hz), 6.94-7.00 (m, 1H), 7.03-7.08 (m, 2H), 7.25-7.32 (m, 1H), 7.39-7.46 (m, 2H), 7.90-8.01 (m, 2H), 8.05 (s, 1H), 8.50 (d, 1H, J=8.5 Hz); LCMS 344 (M+H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 3.5h;
146
Example 146:; EPO 146To a dichloromethane solution (5 mL) of 143 (145 mg, 0.580 mmol) was added benzo[B]thiophene-2- carbonyl chloride (171 mg, 0.870 mmol), triethylamine (176 mg, 1.74 mmol) and 4- (dimethylamino)pyridine (7 mg, 0.058 mmol). The mixture was stirred at room temperature for 3.5 hours. It was then evaporated. The residue was dissolved in ethyl acetate (30 mL). The ethyl acetate solution was washed with water (20 mL), cold 1 M HCI (20 mL), cold 5% sodium bicarbonate (20 mL) and brine (20 mL), dried with Na2SO4 and concentrated. After column chromatography (10-20% ethyl acetate in hexane), the title compound was obtained in 94% yield.1H NMR (CDCI3): δ 7.66-7.56 (3H, m), 7.26-7.15 (1 H, m), 7.03-6.95 (1 H, m), 6.72-6.61 (2H, m), 4.89- 4.80 (1 H, m), 4.14-3.99 (2H, m), 3.27-3.18 (2H, m), 1.13-1.01 (3H, m). LCMS (API-ES): 411.1 (M+H+).
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; 3-(1H-benzoimidazol-2-yl)-alanine With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
11
Example 11 :; To an acetonitrile/water solution (4 ml_/5 ml_) of 9 (236 mg, 0.977 mmol) was added benzo[B]thiophene-2-carbonyl chloride (192 mg, 0.977 mmol) and sodium carbonate (362 mg, 3.42 mmol). The mixture was stirred at room temperature for overnight. It was then acidified with 1 M HCI. Solids was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 81% yield. 1H NMR (DMSO- d6): δ 12.57 (1 H, brs), 9.16 (1 H, d, J=7.83 Hz), 8.06 (1 H, s), 7.95 (1 H, d, J=7.33 Hz), 7.89 (1 H, d, J=8.59 Hz), 7.45-7.33 (4H, m), 7.08-7.02 (2H, m), 4.93 (1 H, dd, J=15.92, 8.09 Hz), 3.41 (1 H, dd, J=15.41 , 6.06 Hz), 3.28 (1 H, dd, J=15.42, 8.34 Hz). LCMS (APCI): 366.1 (M+H+). Elemental Analysis for (C19H15N3O3S) calc: C 62.45, H 4.14, N 11.50; found: C 62.23, H 4.21 , N 11.48.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; 3-(2-benzimidazolyl)-D-alanine With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
14
Example 14:; To an acetonitrile/water solution (4 mL/5 mL) of 13a (213 mg, 0.882 mmol) was added benzo[B]thiophene-2-carbonyl chloride (173 mg, 0.882 mmol) and sodium carbonate (327 mg, 3.09 mmol). The mixture was stirred at room temperature overnight. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 84% yield. 1H NMR (DMSO-c/6): δ 9.38 (1 H, d, J=7.84 Hz), 8.29 (1 H, s), 8.17 (1 H, d, J=8.59 Hz), 8.12 (1 H, d, J=6.32 Hz), 7.68-7.56 (4H, m), 7.31 -7.24 (2H, m), 5.16 (1 H, dd, J=15.92, 8.09 Hz), 3.63 (1 H, dd, J=15.16, 5.81 Hz), 3.51 (1 H, dd, J=15.41 , 8.33 Hz). LCMS (APCI): 366.0 (M+H+). Elemental Analysis for (C19H15N3O3S) calc: C 62.45, H 4.14, N 11.50; found: C 62.30, H 4.32, N 11.50.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C10H10FN3O2 With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
17
Example 17:; To an acetonitrile/water solution (3 ml_/4 mL) of 16a (223 mg, 0.859 mmol) was added benzo[B]thiophene-2-carbonyl chloride (169 mg, 0.859 mmol) and sodium carbonate (319 mg, 3.01 mmol). The mixture was stirred at room temperature overnight. It was then acidified with 1 M HCI. Solid was collected by filtration and washed with water (2X) and ethyl acetate (2X) to give the title compound in 85% yield. 1H NMR (DMSO-D6): δ 9.27-9.16 (1 H, m), 8.13 (1H, s), 8.06-7.93 (2H, m), 7.52-7.40 (3H, m), 7.36-7.27 (1H, m), 7.03-6.93 (1H, m), 5.04-4.96 (1 H, m), 3.52-3.31 (2H, m). LCMS (APCI): 384.0 (M+H+). Elemental Analysis for (C19H14FN3O3S) calc: C 59.52, H 3.68, N 10.96; found: C 59.57, H 3.83, N 10.86.
Stage #1: benzo<b>thiophene-2-carboxylic acid chloride; C10H11N3O2*ClH With sodium carbonate In water; acetonitrile at 20℃;
Stage #2: With hydrogenchloride In water; acetonitrile
2
Example 2:; To an acetonitrile/water solution (4 mL /5 mL ) of aminoacid 1a (296 mg, 1.23 mmol) was added benzo[B]thiophene-2-carbonyl chloride (241 mg, 1.23 mmol) and sodium carbonate (456 mg, 4.31 mmol). The mixture was stirred at room temperature for overnight. It was then acidified with 1M HCI. Solids were filtered and washed with water (2x) and ethyl acetate (2x) to give the title compound in 76% yield. 1H NMR (DMSO-D6): δ 9.17 (1 H, d, J=7.72 Hz), 8.06 (1 H, s), 7.99-7.85 (2H, m), 7.47- 7.32 (4H, m), 7.10-7.00 (2H, m), 4.94 (1H, dd, J=13.94, 8.10 Hz), 3.46-3.23 (2H, m). LCMS (AP-ESI): 366.2 (M+H+). Elemental Analysis for (C19H15N3O3S03.H2O) calc: C 61.54, H 4.24, N 11.33; found: C 61.57, H 4.23, N 11.21.
With triethylamine In ISOPROPYLAMIDE at 40℃; for 48h;
1.b3
(b3) Synthesis of methyl (2S)-3-(4-alkyl/aryl carbonyl/sulphonyl phenyl)-2- [methoxy(oxo)acetyl]amino}propanoate (compounds A 7 DME to Al 2 DME, BlJ)ME- B3_DME, B12_DME and ClJ)ME to C/ 1J)ME)Each reactive building block (see list below in Table 5) was dissolved in dimethylacetamide (1.5 ml) and H-D-tyrosine methyl ester (112.5 mg, 0.4 mmol) was added to each reaction. To these reactions was added triethylamine (55.6 μl, 0.4 mmol) and dimethylaminopyridine (catalytic quantitiy). The mixtures were then stirred and heated (40° C) for 48 hours. Each reaction was purified by Cl 8 reverse phase chromatography.Table 5
With pyridine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
N-(6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)benzo[b]thiophene-2-carboxamide[00173] A 200-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 6-fluoro-2-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.45 g, 13.7 mmol), methylene chloride (85 mL), and pyridine (3 mL) and cooled to 0 0C. To the resulting solution, benzo[b]thiophene-2-carbonyl chloride (2.7 g, 13.7 mmol) was. The reaction was warmed to room temperature and stirred for 1 h. After this time, aqueous HCl (IM, 50 mL) was added to the reaction. The separated aqueous layer was extracted with dichloromethane (2x 25 mL). The combined organics were washed with aqueous HCl (IM, 2 x 5OmL), water (1 x 5OmL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude white solid (5.6 g, 99% yield) was used in the next step without further purification.
With pyridine; In dichloromethane; at 0 - 20℃; for 1.0h;Inert atmosphere;
A 200-mL single-neck round-bottom flask equipped with a magnetic stirrer was purged with nitrogen, charged with <strong>[1227210-37-8]6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline</strong> (S8, 3.45 g, 13.7 mmol), methylene chloride (85 mL), and pyridine (3 mL). After cooling to 0 C, the resulting solution was added with benzo[b]thiophene-2-carbonyl chloride (2.7 g, 13.7 mmol). The reaction mixture was then warmed to room temperature and stirred for 1 h. Subsequently aqueous HCl (1M, 50 mL) was added to the reaction mixture. After separation, the aqueous layer was extracted with dichloromethane (2x 25 mL). Combined organic layers were washed with aqueous HCl (1M, 2 x 50 mL), water (1 x 50 mL) and brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The resulting crude white solid (5.6 g, 99% yield) was used in the next step without further purification.
N-(3-bromopropyl)benzo[b]thiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine In dichloromethane at 20℃;
5 5.1.1. N-(3-Bromopropyl)-3,5-dichlorobenzamide (29a)
General procedure: Compound 28a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide(328 mg, 1.5 mmol was added followed by triethylamine (TEA;0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature.After the reaction was completed, the reaction mixture was dilutedwith CH2Cl2 and sequentially washed with water, 1 N HCl and saturatedNaHCO3. The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane: Ethyl acetate (EtOAc)=4:1 to obtain 29a,(236 mg, 76%) as white solid. Retention factor Rf=0.85 (n-hexane:EtOAc=1:1). Mp=98 °C. 1H NMR (300 MHz, CDCl3): δ 7.62 (d,J=1.8 Hz, 2H), 7.49 (s, J=1.8 Hz, 1H), 6.38 (s, 1H), 3.62 (q,J=6.4 Hz, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.21 (quin, J=6.5 Hz, 2H).
325 mg
With triethylamine In dichloromethane at 20℃;
4 5.1.1. N-(3-Bromopropyl)-3,5-dichlorobenzamide (10a)
General procedure: Compound 9a (191 mg, 1 mmol) was refluxed in excess of thionyl chloride (3 mL) overnight. Excess of thionyl chloride was evaporated and the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide (328 mg, 1.5 mmol was added followed by triethylamine (TEA; 0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was diluted with CH2Cl2 and sequentially washed with water, 1 N HCl and saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. The obtained product was purified by column chromatography with n-hexane/ethyl acetate (EtOAc) = 4:1 to obtain 10a, (236 mg, 76%) as white solid.
4-[5-(2-hydroxyphenyl)-3,4-dihydro-2H-pyrazol-3-yl]-2,6-dimethoxyphenol[ No CAS ]
benzo[b]thiophen-2-yl-[5-(4-hydroxy-3,5-dimethoxyphenyl)-3-(2-hydroxyphenyl)-4,5-dihydropyrazol-1-yl]methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.67%
With pyridine In ethanol at 80℃; for 1h;
3.3. General Procedures for the Synthesis of Compounds b1-19
General procedure: Hydrazine hydrate (0.04 mol, 1.96 g) was added to a solution of compound a1 (0.01 mol,3.00 g) in ethanol (10 mL). The mixture was refluxed under stirring for 4 h, and the reactionmixture was subsequently poured onto crushed ice; the precipitate was filtered out, and productb1 was later crystallized from ethanol. Compounds b2-4 were synthesized following this procedure.Compounds b5-17 were prepared by treating compound b1 (0.01 mol, 3.14 g) with correspondingsubstituted benzoyl chloride or substituted benzenesulfonyl chloride (0.015 mol) at 80 °C in ethanolas solvent with pyridine as catalyst for 1 h to yield the final N-substituted targeted compounds.The N-phenyl-substituted pyrazolines b18 and b19 were prepared by direct cyclization of a1 and a5,respectively, with phenylhydrazine in the presence of TBAB as a catalyst [29].
2-(1-benzothiophene-2-amido)-3,5-dimethylbenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium carbonate; In tetrahydrofuran; water; at 0℃; for 0.5h;
To a 100-mL 3-necked round-bottom flask was placed a solution of <strong>[14438-32-5]2-amino-3,5-dimethylbenzoic acid</strong> (0.973 g,5.89 mmol) in THF (20 mL) and a solution of Na2CO3 (1.79 g,16.73 mmol) in water (20 mL). This was followed by the dropwise addition of 1-benzothiophene-2-carbonyl chloride (1.1 g,5.59 mmol,as prepared above) in THF (20 mL) with stirring at 0C over 30 mm. The resulting solution was stirred for 1H at rt then the reaction was diluted with 20 mL of water and the pH was adjusted to 2 with aqueous 2N HC1.The resulting solution was extracted with EtOAc (3x30 mL) and the organic extracts were combined. The solution was washed with brine (2x20 mL),dried over anhydrous Na2SO4,and concentrated under reduced pressure affording 1 g (55%) of the title compound as a yellow solid. Mass Spectrum (LCMS,ESI neg): Calcd. for C18H16NO3S: 324.1 (M-H); Found: 324.
300 mg (0.581 mmol) of <strong>[3482-49-3]fusidic acid</strong> and 142 mg (1.161 mmol) of 4-dimethylaminopyridine (DMAP) were first weighed in a 50 mL magnetron-containing round bottom flask,Under nitrogen protection, measure 10 mL of ultra-dried anhydrous methylene chloride in a flask, and stir at room temperature under nitrogen for about 15 minutes until it is completely dissolved.0.94 mL (1.161 mmol) of pyridine was added via syringe, stirred for about 20 min at room temperature under nitrogen, and finally 0.34 mL (1.743 mmol) of benzothiophene-2-carbonyl chloride was added three times at room temperature under nitrogen protection. The reaction was stirred for 2 h.The end point of the reaction was checked by TLC (developer: dichloromethane:ethyl acetate=3:1, coloring agent: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio)=85:10:5:0.5), and the reaction was completed. The crude product of compound FA-E-16 was obtained by washing and extractive drying and the like, and purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate=6:1) to give compound FA-E-16, which The molecular structure is shown in Fig. 16. White solid, Rf = 0.37 (developer: dichloromethane:ethyl acetate = 3:1), yield: 68%.
methyl 3-(benzo[b]thiophen-2-yl)-3-oxo-2-phenylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: benzeneacetic acid methyl ester With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran; hexane at -78℃; for 0.166667h;
Stage #2: benzo<b>thiophene-2-carboxylic acid chloride In tetrahydrofuran; hexane at -78 - 20℃;
3-Substituted 4-Aryl-5-hydroxyisoxazoles/4-Arylisoxazol-5(4H)-ones 6; General Procedure A (Scheme 6)
General procedure: A solution of 2.5 M n-BuLi in hexane (1.2 equiv) was added dropwise to a solution of HMDS (1.2 equiv) in anhyd THF at -78 °C under argon, and then, after stirring of the mixture for 10 min, a solution of alkyl 2-arylacetate (1 equiv) in THF was added in one portion. The mixture was stirred for 10 min, after which a solution of acyl chloride (1.15 equiv) in THF was added in one portion and the mixture was stirred for 15 min at -78 °C and then overnight at r.t. The reaction mixture was quenched with sat. aq NH4Cl, extracted with EtOAc or Et2O, and the organic layer was washed with brine and dried over Na2SO4. The solvents were evaporated to give 3-substituted alkyl 2-aryl-3-oxopropanoate 5, which was used without further purification. NH2OH·HCl (2-5 equiv) was added to a solution of 5 in MeOH and the mixture was refluxed for 24 h. The solvent was evaporated, the residue was treated with H2O, and the precipitate that formed was filtered, washed with H2O and a mixture of PE/EtOAc (10:1), and then dried in air to give pure 3-substituted 4-aryl-5-hydroxyisoxazole/4-arylisoxazol-5(4H)-one 6. The yields of 6 were calculated for the two steps, and is based on the starting alkyl 2-arylacetate.
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